Risk of interaction in combination treatment with MAO-inhibitors and tricyclic antidepressants. The

Fråga: Risk of interaction in combination treatment with MAO-inhibitors and tricyclic antidepressants. The importance of treatment sequence.

Sammanfattning: From the literature it is evident that it is dangerous to give an MAO inhibitor and to then add or substitute a tricyclic without an interval of 2-3 weeks. Since some evidence exists suggesting that the opposite response may provoke similar reactions it has been suggested that the two drugs should be initiated simultaneously and at low dosages of both agents.

Svar: Monoamine oxidase (MAO) inhibitors act by irreversibly (or, in the case of phenelzine, competitively) inhibiting MAO enzyme (1). This enzyme, widely distributed in the brain and many other organs, catalyzes the oxidative deamination of noradrenalin, dopamine, serotonin, tyramine and other biogenic amines. Tricyclic antidepressants inhibit the reuptake of monoamines in the presynaptic nerve terminals. Both classes of drugs potentiate the effects of biogenic amines in CNS and their action may be synergistic (2).

The simultaneous administration of tricyclic antidepressants and MAO inhibitors has been associated with a heightened risk of hyperpyrexia, hypertension, cardiac arrythmias and coma (1). Adverse reactions experienced by patients receiving the two types of drugs together or in rapid sequence have been examined in a review by White and Simpson (3). This review and recent case reports (2) indicate that it is hazardous for a patient on chronic treatment with MAO inhibitors to start a treatment with tricyclic antidepressants, without stopping the MAO inhibitors for at least two weeks. Severe, and sometimes fatal, reactions such as hyperthermia, high blood pressure, convulsions and coma are reported after the combination in this sequence. Possible cause of this toxicity is that 2 weeks are needed before new molecules of enzyme, irreversibly, inhibited by MAO inhibitors, are synthesized to restore amine metabolism (4).

The reverse sequence of drugs, adding or substituting MAO inhibitory to an established course of tricyclic antidepressants, appears to be safer. No fatal reactions but isolated hypertonic, hyperthermic, hypertensive and dyspnoic episodes have been described (3). Recently a controlled trial (5), including 60 patients, has shown that a combined treatment MAO inhibitors-tricyclic antidepressants started at low dosages for both agents and then increased to a maximum of half that used with single drug treatment is safe and effective. No hypertensive or hyperthermic crises occurred in any patients.

With regard to the specific MAO inhibitor used in the combination, tranylcypromine poses substantially greater risk compared to phenelzine and nialamide while among tricyclics serotonin reuptake inhibitory are dangerous in combination. Imipramine and clomipramine have been more often implicated in adverse reactions, while amitriptyline is less dangerous (6).